1. Field of the Invention
The present invention relates generally to a novel method of administering Oxybutynin, and to novel forms of Oxybutynin and novel dosage forms containing Oxybutynin adapted for pulmonary route. The invention will be described in particular in connection with pulmonary delivery of Oxybutynin for treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), although other uses such as prophylactic, therapeutic or ameliorative treatment of incontinence and intestinal hypermotility, i.e. irritable bowel syndrome, also are contemplated.
2. Description of the Prior Art
Oxybutynin is a racemic compound of the chemical formula 4-diethylaminobut-2-butynyl phenylcyclohexyl-glycolate:

Oxybutynin is an anticholinergic medication that traditionally has been used to treat urinary incontinence, urge incontinence, frequency and over-active bladder symptoms of incontinence (hereinafter singly and collectively referred to as “urge urinary incontinence”). Oxybutynin acts by decreasing muscle spasms of the bladder. It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholine receptor. It also has weaker direct spasmolytic effects on bladder smooth muscle as a calcium antagonist and local anesthetic, but at concentrations far above those used clinically. It is available orally in generic formulation and as the chloride salt, and as the brand-names Ditropan® and Ditropan XL®, and as a transdermal patch under the brand-name Oxytrol®.
Oxybutynin currently is administered in oral formulation as a tablet or multiple tablets and a syrup, or transdermally as a patch or topical gel for treating urge urinary incontinence. However, oral delivery of a therapeutically active amount of Oxybutynin suffers from a number of disadvantages:
(1) Oxybutynin administered in an oral formulation is absorbed from the intestinal track at an undesirably slow and uneven rate with a variable metabolism that leads to undesirable variations in blood levels and undesirably high dosage rates to achieve a therapeutic response leading to undesirable side effects;
(2) Oxybutynin administered in an oral formulation does not produce desirably high blood levels in a desirably short period of time;
(3) Oxybutynin administered in an oral formation may result in a significant amount not reaching targeted tissues because it is being wasted by metabolism or excretion;
(4) Oxybutynin administered in an oral formation is contraindicated for patients with gastrointestinal obstruction disorders because of the risk of urinary retention; and
(5) Oxybutynin administered in oral formulation requires chronic dosing with significant and severe side effects, including dry mouth (xerostomia), constipation, mydriasis, blurred vision, drowsiness, nausea, palpitations, tachycardia and dizziness.
(6) Oxybutynin administered in the oral formulation is subject to first pass metabolism, resulting in the formation of metabolite N-desethyloxybutynin (DEO) which has been attributed to cause the majority of the aforementioned side effects.
As a result, many patients discontinue oral anticholinergic therapy. These adverse effects have been associated with relatively high levels of Oxybutynin's primary metabolite. DEO, which circulates in concentrations approximately 4 (Oxybutynin ER) to 10 (Oxybutynin IR) times that of the parent compound. DEO has been shown to have an greater affinity and binding duration at receptors in the salivary glands than does Oxybutynin. In other words, the metabolite DEO has shown to have a higher side effect-to efficacy ratio than the parent compound Oxybutynin. Levels of DEO in oral and transdermal therapy have been reported to be approximately 10-40 ng/mL and 3 ng/mL, respectively. To completely eliminate the side effect concerns of this drug, it would be advantageous to decrease the DEO levels in systemic circulation to below those found in current therapies (i.e. below 3 ng/mL).
Moreover, there are other disadvantages to current oral administration of Oxybutynin, including:
(7) Oxybutynin administered in an oral formation is administered as a tablet or multiple tablets which may lack the desirable ease of administration because some people may dislike the swallowing of tablets, or may have difficulty swallowing tablets, or are unable to swallow tablets, or may require a liquid to assist swallowing of tablets; and
(8) Oxybutynin-containing tablets also contain several inactive ingredients, including significant amounts of lactose, corn starch, magnesium silicate, magnesium stearate, and talc which may be considered undesirable because some people may dislike or be allergic to one or more of these inactive ingredients that comprise the Oxybutynin tablets.
Transdermal delivery of Oxybutynin has many of the aforesaid disadvantages. Additionally, some patients suffer skin irritation from transdermal patches, have difficulty maintaining and tolerating patch-to-skin contact, or dislike the aesthetics of a transdermal patch.
Thus, there is a need for improved delivery of Oxybutynin, which will provide enhanced bioavailability, minimized variations in blood levels, and achieve more rapid onset of activity, as compared to oral dosage or transdermal dosage forms, while at the same time providing relative ease of administration and reduced side effects compared to current oral and transdermal delivery methods for administering Oxybutynin.